Project Summary Adaptation is one of the most important and defining properties of all biological systems ranging from a single cell to multi-cellular organisms to populations of interacting species. Adaptation allows living systems to adjust themselves in response to environmental changes and stresses to maintain their normal functions. Therefore, the ability to adapt is crucial for the health and fitness of living systems from human to a single cell. For adaptation at the cellular level, much progresses have been made in identifying key molecular components relevant for adaptation and in measuring the adaptive input-output responses in individual systems. However, despite these advances, many fundamental questions on cellular level adaptation remain unresolved. What are the general system-level molecular mechanisms for adaptation to different types of (chemical and mechanical) stimuli in living cells? Are there any universal design principles governing the underlying biochemical pathways (circuits) that are responsible for the vast variety of adaptive behaviors in cells? In this proposed program, we aim to address these questions broadly to bridge the gap between molecular interactions and system-level adaptation behaviors by using an integrated approach that combines theoretical analysis and computational modeling with quantitative experiments from our experimental collaborators' labs. We plan to study three representative cellular systems: 1) adaptation to chemical signals in bacterium cells (Escherichia coli); 2) adaptation to mechanical signals in bacterial flagellar motor (BFM); 3) adaptation to odor stimuli in olfactory sensory neurons (OSN). In each of these systems, we will develop a system-level model based on known molecular components and their interactions. These system-level models will allow us to verify/falsify different possible molecular mechanisms (hypotheses) against the system level input-output measurements. By comparing the molecular mechanisms for adaptation in these diverse systems, we aim to uncover general features (design principles) in the underlying biochemical pathways (circuits), which should provide a general framework for understanding other cellular adaptation systems such as metal homeostasis, response to osmotic pressure, chemotaxis in Eukaryotic cells, and adaptations of sensory neurons in different sensory modalities.